Ação da melatonina no microambiente tumoral anaeróbico verificada por marcadores de hipóxia e metabolismo energético em modelo experimental de câncer de mama
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da FAMERP |
Texto Completo: | http://bdtd.famerp.br/handle/tede/479 |
Resumo: | Breast cancer is the most common cancer among women and has a high mortality rate. The rapid tumor growth hinders the infusion of O2, mainly in the central region of the tumor, thus, adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can be used to control these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects has demonstrated important anti-tumor actions and recently has been associated with the control of hypoxia and Warburg effect. Objetives - In this study, we evaluated the action of melatonin on cell viability, tumor growth and tumor metabolism evaluated by different markers of hypoxia and energy metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer in vitro and in vivo model. Methods - In vitro cell viability was investigated by the MTT (methyl-thiazole-tetrazolium) assay and gene and protein expressions by quantitative real-time PCR and immunocytochemistry, respectively. Melatonin effects were tested in vivo, using athymic nude mice injected with MDA-MB-231 cells (xenograft model). Tumor growth and necrosis were evaluated by images obtained by positron emission tomography (PET / CT). Results - Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and controls tumor growth and necrosis in Balb/c nude mice (p <0.05). The treatment also decreased HIF-1α gene and protein expression, concomitantly with the expression of energy metabolism markers (p <0.05). Conclusion - Taken together, these results show that melatonin down-regulates HIF-1α expression and consequently, it can regulates energy metabolism markers (GLUT-1, GLUT-3, CA-IX and CA-XII) in breast tumor cells, controlling hypoxia and tumor progression. |
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Zuccari, Debora Aparecida Pires de Camposhttp://lattes.cnpq.br/3299100010535257Silveira, Márcia Maria Chiquitelli Marqueshttp://lattes.cnpq.br/7852430432457471Souza, Dorotéia Rossi da Silvahttp://lattes.cnpq.br/395525709362467138241023820http://lattes.cnpq.br/6553509883448200Mota, André de Lima2018-11-14T17:38:48Z2017-07-14Mota, André de Lima. Ação da melatonina no microambiente tumoral anaeróbico verificada por marcadores de hipóxia e metabolismo energético em modelo experimental de câncer de mama. 2017. 98 f. Dissertação (Programa de Pós-Graduação em Ciências da Saúde) - Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto.1313http://bdtd.famerp.br/handle/tede/479Breast cancer is the most common cancer among women and has a high mortality rate. The rapid tumor growth hinders the infusion of O2, mainly in the central region of the tumor, thus, adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can be used to control these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects has demonstrated important anti-tumor actions and recently has been associated with the control of hypoxia and Warburg effect. Objetives - In this study, we evaluated the action of melatonin on cell viability, tumor growth and tumor metabolism evaluated by different markers of hypoxia and energy metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer in vitro and in vivo model. Methods - In vitro cell viability was investigated by the MTT (methyl-thiazole-tetrazolium) assay and gene and protein expressions by quantitative real-time PCR and immunocytochemistry, respectively. Melatonin effects were tested in vivo, using athymic nude mice injected with MDA-MB-231 cells (xenograft model). Tumor growth and necrosis were evaluated by images obtained by positron emission tomography (PET / CT). Results - Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and controls tumor growth and necrosis in Balb/c nude mice (p <0.05). The treatment also decreased HIF-1α gene and protein expression, concomitantly with the expression of energy metabolism markers (p <0.05). Conclusion - Taken together, these results show that melatonin down-regulates HIF-1α expression and consequently, it can regulates energy metabolism markers (GLUT-1, GLUT-3, CA-IX and CA-XII) in breast tumor cells, controlling hypoxia and tumor progression.O câncer de mama é o mais comum entre as mulheres, e apresenta alta taxa de mortalidade. O rápido crescimento tumoral dificulta a perfusão de O2, principalmente na região central do tumor, assim condições adversas no microambiente tumoral, como hipóxia e acidose, podem exercer pressão seletiva no microambiente tumoral, selecionando subpopulações de células tumorais com vantagens para sobrevivência em tal ambiente. Neste contexto, agentes terapêuticos com potencial para serem utilizados no controle destas condições precisam ser explorados. A melatonina, além de seus efeitos fisiológicos tem demonstrado importantes ações antitumorais e, recentemente, tem sido associada ao controle da hipóxia e do efeito Warburg em células tumorais. Objetivos – Avaliar a ação da melatonina na viabilidade celular, crescimento tumoral e no controle do metabolismo do tumor, verificado através da expressão de marcadores relacionados à hipóxia e metabolismo energético (HIF-1α, transportadores de glicose GLUT-1, GLUT-3 e anidrases carbônicas IX e XII), em modelos in vitro e in vivo de câncer de mama triplo negativo. Métodos - A viabilidade celular in vitro foi investigada pelo ensaio MTT (methyl-thiazol-tetrazolium) e a expressão gênica e proteica por meio de PCR em tempo real e imunocitoquímica, respectivamente. A ação da melatonina foi verificada in vivo, utilizando camundongos Balb/c nude atímicos inoculados com células MDA-MB-231 (modelo de xenoenxerto). Crescimento tumoral e necrose foram avaliados por imagens obtidas por tomografia por emissão de pósitrons (PET/CT). Resultados - O tratamento com melatonina reduziu a viabilidade das células MDA-MB-231 e controlou o crescimento tumoral e necrose em camundongos Balb/c nude (p < 0,05). O tratamento também diminuiu a expressão gênica e proteica de HIF-1α concomitantemente com a expressão dos marcadores do metabolismo energético (p < 0,05). Conclusão - Tomados em conjunto, estes resultados mostram que a melatonina regula negativamente a expressão de HIF-1α e consequentemente, atua na regulação dos marcadores do metabolismo energético (GLUT-1, GLUT-3, CA-IX and CA-XII) em células de tumor de mama, controlando a hipóxia e progressão tumoral.Submitted by Suzana Dias (suzana.dias@famerp.br) on 2018-11-14T17:38:48Z No. of bitstreams: 1 AndreLimaMota_dissert.pdf: 1518771 bytes, checksum: b714afeb6a7e8b4402064df4eba2523f (MD5)Made available in DSpace on 2018-11-14T17:38:48Z (GMT). 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dc.title.por.fl_str_mv |
Ação da melatonina no microambiente tumoral anaeróbico verificada por marcadores de hipóxia e metabolismo energético em modelo experimental de câncer de mama |
title |
Ação da melatonina no microambiente tumoral anaeróbico verificada por marcadores de hipóxia e metabolismo energético em modelo experimental de câncer de mama |
spellingShingle |
Ação da melatonina no microambiente tumoral anaeróbico verificada por marcadores de hipóxia e metabolismo energético em modelo experimental de câncer de mama Mota, André de Lima Breast Neoplasms Tumor Hypoxia Neoplasias da Mama Hipoxia Tumoral CIENCIAS DA SAUDE::8765449414823306929::600 |
title_short |
Ação da melatonina no microambiente tumoral anaeróbico verificada por marcadores de hipóxia e metabolismo energético em modelo experimental de câncer de mama |
title_full |
Ação da melatonina no microambiente tumoral anaeróbico verificada por marcadores de hipóxia e metabolismo energético em modelo experimental de câncer de mama |
title_fullStr |
Ação da melatonina no microambiente tumoral anaeróbico verificada por marcadores de hipóxia e metabolismo energético em modelo experimental de câncer de mama |
title_full_unstemmed |
Ação da melatonina no microambiente tumoral anaeróbico verificada por marcadores de hipóxia e metabolismo energético em modelo experimental de câncer de mama |
title_sort |
Ação da melatonina no microambiente tumoral anaeróbico verificada por marcadores de hipóxia e metabolismo energético em modelo experimental de câncer de mama |
author |
Mota, André de Lima |
author_facet |
Mota, André de Lima |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Zuccari, Debora Aparecida Pires de Campos |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/3299100010535257 |
dc.contributor.referee1.fl_str_mv |
Silveira, Márcia Maria Chiquitelli Marques |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/7852430432457471 |
dc.contributor.referee2.fl_str_mv |
Souza, Dorotéia Rossi da Silva |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/3955257093624671 |
dc.contributor.authorID.fl_str_mv |
38241023820 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/6553509883448200 |
dc.contributor.author.fl_str_mv |
Mota, André de Lima |
contributor_str_mv |
Zuccari, Debora Aparecida Pires de Campos Silveira, Márcia Maria Chiquitelli Marques Souza, Dorotéia Rossi da Silva |
dc.subject.eng.fl_str_mv |
Breast Neoplasms Tumor Hypoxia |
topic |
Breast Neoplasms Tumor Hypoxia Neoplasias da Mama Hipoxia Tumoral CIENCIAS DA SAUDE::8765449414823306929::600 |
dc.subject.por.fl_str_mv |
Neoplasias da Mama Hipoxia Tumoral |
dc.subject.cnpq.fl_str_mv |
CIENCIAS DA SAUDE::8765449414823306929::600 |
description |
Breast cancer is the most common cancer among women and has a high mortality rate. The rapid tumor growth hinders the infusion of O2, mainly in the central region of the tumor, thus, adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can be used to control these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects has demonstrated important anti-tumor actions and recently has been associated with the control of hypoxia and Warburg effect. Objetives - In this study, we evaluated the action of melatonin on cell viability, tumor growth and tumor metabolism evaluated by different markers of hypoxia and energy metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer in vitro and in vivo model. Methods - In vitro cell viability was investigated by the MTT (methyl-thiazole-tetrazolium) assay and gene and protein expressions by quantitative real-time PCR and immunocytochemistry, respectively. Melatonin effects were tested in vivo, using athymic nude mice injected with MDA-MB-231 cells (xenograft model). Tumor growth and necrosis were evaluated by images obtained by positron emission tomography (PET / CT). Results - Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and controls tumor growth and necrosis in Balb/c nude mice (p <0.05). The treatment also decreased HIF-1α gene and protein expression, concomitantly with the expression of energy metabolism markers (p <0.05). Conclusion - Taken together, these results show that melatonin down-regulates HIF-1α expression and consequently, it can regulates energy metabolism markers (GLUT-1, GLUT-3, CA-IX and CA-XII) in breast tumor cells, controlling hypoxia and tumor progression. |
publishDate |
2017 |
dc.date.issued.fl_str_mv |
2017-07-14 |
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2018-11-14T17:38:48Z |
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Mota, André de Lima. Ação da melatonina no microambiente tumoral anaeróbico verificada por marcadores de hipóxia e metabolismo energético em modelo experimental de câncer de mama. 2017. 98 f. Dissertação (Programa de Pós-Graduação em Ciências da Saúde) - Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto. |
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http://bdtd.famerp.br/handle/tede/479 |
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1313 |
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Mota, André de Lima. Ação da melatonina no microambiente tumoral anaeróbico verificada por marcadores de hipóxia e metabolismo energético em modelo experimental de câncer de mama. 2017. 98 f. Dissertação (Programa de Pós-Graduação em Ciências da Saúde) - Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto. 1313 |
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